Stimulation of thymus for vaccination development

Abstract

The present disclosure provides methods for enhancing the response of a patient's immune system to vaccination. This is accomplished by reactivating the thymus. Optionally, hematopoietic stem cells, autologous, syngeneic, allogeneic or xenogeneic, are delivered to increase the speed of regeneration of the patient's immune system. In one embodiment the hematopoietic stem cells are CD34 + . The patient's thymus is reactivated by disruption of sex steroid mediated signaling to the thymus. In one embodiment, this disruption is created by administration of LHRH agonists, LHRH antagonists, anti-LHRH receptor antibodies, anti-LHRH vaccines or combinations thereof.

1 - 14  (Cancelled)  
     
     
         15 . A method for improving an immune response to a vaccine antigen in a patient, comprising: 
 reactivating the thymus of the patient; and    administering a vaccine to the patient, the vaccine comprising a vaccine antigen,    wherein the patient develops an immune response to the vaccine antigen.    
     
     
         16 . The method of  claim 15 , wherein the thymus of the patient has been at least in part atrophied before it is reactivated.  
     
     
         17 . The method of  claim 16 , wherein the patient has a disease that at least in part atrophied the thymus of the patient.  
     
     
         18 . The method of  claim 16 , wherein the patient has had a treatment of a disease that at least in part atrophied the thymus of the patient.  
     
     
         19 . The method of  claim 18 , wherein the treatment is immunosuppression, chemotherapy, or radiation treatment.  
     
     
         20 . The method of  claim 16 , wherein the patient is post-pubertal.  
     
     
         21 . The method of  claim 15 , further comprising administering cells to the patient, wherein the cells are stem cells, progenitor cells, or combinations thereof.  
     
     
         22 . The method of  claim 21 , wherein the stem cells are selected from the group consisting of hematopoietic stem cells, epithelial stem cells, and combinations thereof.  
     
     
         23 . The method of  claim 21 , wherein the progenitor cells are selected from the group consisting of lymphoid progenitor cells, myeloid progenitor cells, and combinations thereof.  
     
     
         24 . (Cancelled)  
     
     
         25 . The method of  claim 22 , wherein the cells are hematopoietic stem cells.  
     
     
         26 . The method of  claim 25 , wherein the hematopoietic stem cells are CD34 + .  
     
     
         27 . The method of  claim 21 , wherein the cells are autologous.  
     
     
         28 . The method of  claim 21 , wherein the cells are not autologous.  
     
     
         29 . The method of  claim 25 , wherein the hematopoietic stem cells are administered when the thymus begins to reactivate.  
     
     
         30 . The method of  claim 15 , wherein the thymus is reactivated by disruption of sex steroid-mediated signaling to the thymus.  
     
     
         31 . The method of  claim 30 , further comprising administering cells to the patient, wherein the cells are stem cells, progenitor cells, or combinations thereof.  
     
     
         32 . The method of  claim 31 , wherein the stem cells are selected from the group consisting of hematopoietic stem cells, epithelial stem cells, and combinations thereof.  
     
     
         33 . The method of  claim 31 , wherein the progenitor cells are selected from the group consisting of lymphoid progenitor cells, myeloid progenitor cells, and combinations thereof.  
     
     
         34 . (Cancelled)  
     
     
         35 . The method of  claim 32 , wherein the cells are hematopoietic stem cells.  
     
     
         36 . The method of  claim 31 , wherein the cells are administered at the time disruption of sex steroid-mediated signaling to the thymus is begun.  
     
     
         37 . The method of  claim 30 , wherein the sex steroid-mediated signaling to the thymus is disrupted by surgical castration.  
     
     
         38 . The method of  claim 30 , wherein the sex steroid-mediated signaling to the thymus is disrupted by chemical castration.  
     
     
         39 . The method of  claim 30 , wherein the sex steroid-mediated signaling to the thymus is disrupted by administration of a pharmaceutical.  
     
     
         40 . The method of  claim 39 , wherein the pharmaceutical is selected from the group consisting of LHRH agonists, LHRH antagonists, anti-LHRH vaccines, anti-androgens, anti-estrogens, SERMs, SARMs, SPRMs, ERDs, aromatase inhibitors, anti-progestogens, Dioxalan derivatives and combinations thereof.  
     
     
         41 . The method of,  claim 40 , wherein the LHRH agonists are selected from the group selected from the group consisting of Goserelin, Lupron, Leuprolide, Triptorelin, Meterelin, Buserelin, Histrelin, Nafarelin, Lutrelin, Leuprorelin, Deslorelin, Cystorelin, Decapeptyl, Gonadorelin, and combinations thereof.  
     
     
         42 . The method of  claim 40 , wherein the LHRH antagonists are selected from the group consisting of Abarelix, Cetrorelix, and combinations thereof.  
     
     
         43 . The method of  claim 15 , wherein patient's immune response to the vaccine antigen is improved compared to that immune response which would have otherwise occurred in a patient prior to thymus reactivation.  
     
     
         44 . The method of  claim 15 , wherein the vaccine is a therapeutic vaccine or a prophylactic vaccine.  
     
     
         45 . The method of  claim 15 , wherein the vaccine antigen is an antigen from an agent, wherein the agent is selected from the group consisting of a virus, a bacterium, a fungus, a parasite, a prion, a cancer, an allergen, an asthma-inducing agent, a “self” protein and an antigen which causes an autoimmune disease.  
     
     
         46 . The method of  claim 45 , wherein the agent is a virus.  
     
     
         47 . The method of  claim 46 , wherein the virus is selected from the group consisting of Retroviridae, Picornaviridae, Calciviridae, Togaviridae, Flaviridae, Coronaviridae, Rhabdoviridae, Filoviridae, Paramyxoviridae, Orthomyxoviridae, Bungaviridae, Arenaviridae, Reoviridae, Birnaviridae, Hepadnaviridae, Parvoviridae, Papovaviridae, Adenoviridae, Herpesviridae, Poxviridae, and Iridoviridae.  
     
     
         48 . The method of  claim 46 , wherein the virus is selected from the group consisting of influenza virus, human immunodeficiency virus, and herpes simplex virus.  
     
     
         49 . The method of  claim 45 , wherein the agent is a bacterium.  
     
     
         50 . The method of  claim 41 , wherein the bacterium is selected from the group consisting of  Helicobacter pylori, Borelia burgdorferi, Legionella pneumophilia, Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium kansaii, Mycobacterium gordonae, Mycobacteria sporozoites, Staphylococcus aureus, Neisseria gonorrhoeae, Neisseria meningitidis, Listeria monocytogenes, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus faecalis, Streptococcus bovis, Streptococcus pneumoniae , pathogenic  Campylobacter  sporozoites,  Enterococcus  sporozoites,  Haemophilus influenzae, Bacillus anthracis, Corynebacterium diphtheriae, Corynebacterium  sporozoites,  Erysipelothrix rhusiopathiae, Clostridium perfringens, Clostridium tetani, Enterobacter aerogenes, Klebsiella pneumoniae, Pasturella multocida, Bacteroides  sporozoites,  Fusobacterium nucleatum, Streptobacillus moniliformis, Treponema pallidium, Treponema pertenue, Leptospira , and  Actinomyces israelli.    
     
     
         51 . The method of  claim 49 , wherein the bacterium is a mycobacterium.  
     
     
         52 . The method of  claim 45 , wherein the agent is a parasite.  
     
     
         53 . The method of  claim 52 , wherein the parasite is selected from the group consisting of  Plasmodium falciparum, Plasmodium yoelli , and  Toxoplasma gondii.    
     
     
         54 . The method of  claim 52 , wherein the parasite is a malaria parasite.  
     
     
         55 . The method of  claim 45 , wherein the agent is an infectious fungus.  
     
     
         56 . The method of  claim 55 , wherein the infectious fungus is selected from the group consisting of  Cryptococcus neoformans, Histoplasma capsulatum, Coccidioides immitis, Blastomyces dermatitidis, Chlamydia trachomatis, Candida albicans.    
     
     
         57 . The method of  claim 45 , wherein the agent is a cancer or tumor.  
     
     
         58 . The method of  claim 57 , wherein the cancer is selected from the group consisting of a cancer of the brain, a cancer of the lung, a cancer of the ovary, a cancer of the breast, a cancer of the prostate, a cancer of the colon, a cancer of the blood, a carcinoma, a melanoma and a sarcoma.  
     
     
         59 . The method of  claim 45 , wherein the agent is an allergen.  
     
     
         60 . The method of  claim 59 , wherein the allergen causes an allergic condition selected from the group consisting of eczema, allergic rhinitis, allergic coryza, hay fever, bronchial asthma, urticaria (hives), and food allergies.  
     
     
         61 - 62 . (Cancelled)  
     
     
         63 . The method of  claim 15 , wherein the vaccine is selected from the group consisting of killed vaccines, inactivated vaccines, attenuated vaccines, recombinant vaccines, subunit vaccines, and DNA vaccines.  
     
     
         64 . The method of  claim 15 , wherein the vaccine is administered when the thymus begins to reactivate.  
     
     
         65 . The method of  claim 30 , wherein the vaccine is administered at the time disruption of sex steroid-mediated signaling to the thymus is begun.  
     
     
         66 . The method of  claim 15 , further comprising administering a cytokine, a growth factor, or a combination of a cytokine and a growth factor to the patient.  
     
     
         67 . The method of  claim 66 , wherein the cytokine is selected from the group consisting of Interleukin 2 (IL-2), Interleukin 3 (IL-3), Interleukin 4 (IL-4), Interleukin 6 (IL-6), Interleukin 7 (IL-7), Interleukin 15 (IL-15), Interferon gamma (IFN-γ), and combinations thereof.  
     
     
         68 . The method of  claim 66 , wherein the growth factor is selected from the group consisting of members of the epithelial growth factor family, members of the fibroblast growth factor family, stem cell factor, granulocyte colony stimulating factor (G-CSF), keratinocyte growth factor (KGF), insulin-like growth factor-1 (IGF-1), and combinations thereof.  
     
     
         69 - 71 . (Cancelled)  
     
     
         72 . A method for enhancing transplantation of donor hematopoietic stem cells into the thymus of a recipient patient, comprising: 
 depleting the T cells of the patient;    reactivating the thymus of the patient; and    transplanting donor hematopoietic stem cells to the patient,    wherein uptake of the donor hematopoietic stem cells into the patient's thymus is enhanced as compared to the uptake that would have otherwise occurred in a patient prior to thymus reactivation.    
     
     
         73 . A method for increasing virus-specific peripheral T cell responsiveness of a patient with an at least partially atrophied thymus, comprising: 
 reactivating the thymus of the patient;    exposing the patient to a virus; and    determining the virus-specific peripheral T cell responsiveness in the patient,    wherein the patient has an increased viral-specific peripheral T cell responsiveness as compared to the responsiveness that would have otherwise occurred in a patient prior to thymus reactivation.    
     
     
         74 . The method of  claim 30 , wherein the sex steroid-mediated signaling to the thymus is disrupted by lowering the level of sex steroid hormones.  
     
     
         75 . The method of  claim 15 , wherein the method further comprises administering an adjuvant to the patient.  
     
     
         76 . The method of  claim 40 , wherein the anti-androgen is Eulexin or ketoconazole.